Vioxx and the coxib controversy

Science.Ars returns this weekend with some tasty tidbits from the world of …

It probably hasn't escaped anyone that Merck had to withdraw one of their blockbuster drugs, Vioxx, last week. A little bit of background first. The most commonly prescribed class of drugs that includes aspirin, ibuprofen and other NSAIDs (non steroidal anti inflammatory drugs) work by blocking an enzyme called cyclooxygenase (COX). There are two forms of the enzyme, COX-1 and COX-2. COX-1 is expressed in lots of cells all the time, notably the lining of the stomach, where it regulates acid production. COX-2, on the other hand, was thought responsible for the bad effects of this enzyme, and is not present in most cells normally, only appearing when things are going wrong. Bright minds working in research looked at the high number of hospitalizations resulting from NSAID-induced gastrointestinal damage and thought "what if we had a drug that only blocked the bad enzyme (COX-2) and left the one in the stomach (COX-1) alone? In 1999 we had our first answer as Celebrex (Pfizer) made it to the market, followed shortly by Vioxx. Very shortly both drugs made it into the top 20 sales chart, with Vioxx being prescribed to over 10 million patients in the US alone.

Unfortunately for Merck, and possibly Pfizer, it turns out that COX-2 isn't just bad. In addition to its role in inflammation, it also plays an important part in controlling the cardiovascular system ? stopping platelets from forming thrombi, preventing damage to vessels, that kind of thing. Not the sort of thing you want to stop, especially in the patient group these drugs are marketed at. Data from clinical trials had been conflicting on the cardiovascular side effects up until now, but a trial involving Vioxx and colorectal cancer had to be stopped after a huge increase in the amount of heart attacks and strokes compared to placebo.

Merck hurriedly withdrew their drug from the global market, although Pfizer claims that "each Cox-2 inhibitor has a distinct chemical structure and we would not expect them to have the same side effect profile." As someone working in this particular field, I'm not so sure that will prove to be the case, and we may yet see the other coxibs being withdrawn from sale. The New England Journal of Medicine even went as far as publishing two articles on the matter online ? ahead of print ? regarding the withdrawal. They draw attention to current system by which drugs are approved for use by the FDA and lack of transparency from the pharmaceutical industry. Data suggesting the possible cardiovascular side effects of Vioxx, and coxibs as a class of drug, have been in the public domain for several years, yet at no point did the FDA ask for clinical trials to elucidate the matter.

Two years after approving the drug for use in humans, an FDA advisory committee suggested that the increase in cardiovascular side effects warranted a new clinical trial to determine the risk, especially given that the target patient group (osteoarthritis) frequently had coexisting cardiovascular disease. Instead Merck began a media blitz, releasing press release after press release and spending US$100 million a year on direct to consumer marketing to assure that Vioxx was safe. Coming on the heels of the recent hearings over the prescribing of SSRIs to children, this must only raise further questions over the FDA and whether in recent years it has become too close to the drug companies it is intended to regulate.

California to push stem cell funding initiative

Embryonic stem cell research is back in the headlines, again. The state of California is putting forward a ballot initiative, Proposition 71, to raise US$300 million through a bond issue and to use that money to fund research into human embryonic stem cells, and protect the right to do so in the state constitution. With the issue high on the agenda in the upcoming presidential election, and high-profile backers like the Michael J Fox and the late Christopher Reeve, it will be interesting to see how Californians respond at the ballot box.

1918 flu pandemic

Influenza is another hot topic these days. From avian flu jumping from person to person, to the shutting down of Chiron by the UK halving the amount of available vaccine for the US this winter, it looks as though influenza will remain on the mind of the public throughout the winter. Bad colds are often mistaken for influenza, leading to a perception amongst many that it's a fairly harmless disease, and while recent strains have not been terribly lethal, that isn't always the case.

Interesting research from a group based in Wisconsin and Tokyo has shed new light (subscription required) on just how the 1918-19 flu pandemic was able to kill 20 million people. Prof. Kawaoka's group sequenced the haemagglutinin and neuroaminidase genes from the 1918 strain and compared them to current strains, and discovered a much greater virulence in 1918 strain. In addition to the high virulence, that strain also had the ability to infect deeper into the lung, which correlates with the much greater mortality. Their work helps us in further understanding the workings of this virus that has the potential to cause so much damage to our society.

Square bacteria

William Kent (or perhaps William Blake) once said "nature abhors a straight line." That might not be so true. First identified in 1980, Walsby's square bacteria (named for its discoverer, a British microbiologist) are a species of extremophile that grow in very high salt concentrations, and instead of the common round or rod shapes we often find such microbes, these ones are square. For the first time, scientists in Melbourne, Australia have been able to grow them in the lab. Most organisms cannot tolerate salty solutions well, as any slug or snail could well attest. It draws the water out of their cells and they shrivel and die. Haloquadratum walsby, however, needs 18% salt (similar to soy sauce) to grow, and takes up to 48 hours to double in population, much slower than the 20 minutes or so needed by E. Coli.

Shh, Don't wake the dinosaur

The link between birds and dinosaurs grew stronger this week, with the announcement of the discovery of 135 million year old fossil in China. Called Mei Long (soundly sleeping dragon), the duck-sized fossil was discovered almost complete, and in a repose that suggested it was fast asleep when it met its end. The dinosaur was curled up in the "tuck in" pose, commonly seen in birds. Mei Long didn't have wings however, and we still can't say definitively whether or not they were warm blooded. At the same time, it is exciting to see a fossilized animal in a life pose, and Mark Norell, one of the discoverers, postulates Mei Long was caught in a volcanic eruption. "There's lots of ash in the sediments," he says. "But it also could have been poisoned by noxious gas such as carbon monoxide. It's hard to show."